The overall objective of the project relates to gaining an understanding of the mechanisms of the replication of Marek's disease herpesvirus genome in cells productively infected with the virus and in lymphorid tumor cells which harbor resident viral genomes. Phosphonoacetate (PA) is a highly effective inhibitor of herpesvirus replication by blocking herpesvirus DNA synthesis through inhibition of the viral induced DNA polymerase. We have undertaken a study of the mechanism by which PA inhibits the herpesvirus-induced DNA polymerase. From our steady state enzyme kinetic analysis we have concluded that PA interacts with the polymerase of the pyrophosphate binding site. Two models involving PA binding at the pyrophosphate binding site have been considered: (1) the alternate product inhibitor model and the dead-end inhibitor model. No final judgement has been made as to which model is correct. Deoxyribonucleoside-5'-phosphorophosphonoacetate has been synthesized. It is not a substrate or inhibitor for the herpesvirus-induced DNA polymerase. BIBLIOGRAPHIC REFERENCES: Leinbach, S.S., J.M. Reno, L.F. Lee, A.F. Isbell, and J.A. Boezi (1976). Mechanism of Phosphonoacetate Inhibition of Herpesvirus-Induced DNA polymerase. Biochemistry 15, 426. Lee, L.F., K. Nazerian, S.S. Leinbach, J.M. Reno, and J.A. Boezi (1976) Effect of Phosphonoacetate on Marek's Disease Virus Replication. J. of National Cancer Institute 56, 823.